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Title: Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms
Authors: Rossarin Suwanarusk
Bruce Russell
Marina Chavchich
Ferryanto Chalfein
Enny Kenangalem
Varakorn Kosaisavee
Budi Prasetyorini
Kim A. Piera
Marion Barends
Alan Brockman
Usa Lek-Uthai
Nicholas M. Anstey
Emiliana Tjitra
François Nosten
Qin Cheng
Ric N. Price
Charles Darwin University
Australian Army Malaria Institute
Badan Penelitian Dan Pengembangan Kesehatan, Kementerian Kesehatan Republik Indonesia
District Ministry of Health
Mahidol University
Shoklo Malaria Research Unit
John Radcliffe Hospital
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 31-Oct-2007
Citation: PLoS ONE. Vol.2, No.10 (2007)
Abstract: Background. Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined. Methods. Using a modified schizont maturation assay we investigated the in vitro chloroquine susceptibility profile and molecular polymorphisms of P. vivax isolates collected from Papua, Indonesia, where high levels of clinical chloroquine treatment failure have been reported, and from Thailand, where chloroquine treatment is generally effective. Results. The geometric mean chloroquine IC50for P. vivax isolates from Papua (n=145) was 312 nM [95%Cl: 237-411 nM] compared to 46.8 nM [95%Cl: 34.7-63.1 nM] from Thailand (n = 81); p<0.001. Correlating with the known clinical efficacy of the area, a cut off for chloroquine resistance was defined as 220nM, a level exceeded in 13.6% (11/81) of Thai isolates and 65% (94/145) of Papuan isolates; p<0.001. Several sequence polymorphisms in pvcrt-o and pvmdr1, and difference in pvmdr1 copy number were identified. A Y976F mutation in pvmdr1 was present in 96% (123/128) of Papuan isolates and 25% (17/69) of Thai isolates; p<0.001. Overall, the geometric mean chloroquine IC50in isolates with the Y976F mutation was 283 nM [95%Cl: 211-379], compared to 44.5 nM [95%Cl: 31.3-63.4] in isolates with the wild type; p< 0.001. Pvmdr1 amplification occurred in 23% (15/66) of Thai isolates compared to none (0/104) of Indonesian isolates (p<0.001), but was not associated with increased chloroquine resistance after controlling for geographical location. Conclusions. In vitro susceptibility testing of P. vivax discriminates between populations with differing levels of clinical efficacy of chloroquine. The pvmdr1 polymorphism at Y976F may provide a useful tool to highlight areas of emerging chloroquine resistance, although further studies defining its clinical correlates are needed. © 2007 Suwanarusk et al.
ISSN: 19326203
Appears in Collections:Scopus 2006-2010

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